Study of the Efficacy and Safety of Nicotinamide in Patients With Friedreich Ataxia (NICOFA)

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Friedreich ataxia is the most frequent early-onset autosomal recessive hereditary ataxia. It is caused by a pathological expansion of a GAA repeat in the first intron of the frataxin gene (FXN) and results in decreased levels of FXN protein. FXN deficiency results in a relentlessly progressive neurodegenerative condition which frequently presents around puberty. Patients gradually lose coordination, become dysarthric and are frequently wheel-chair bound as adolescents. There is no disease modifying therapy and many patients die prematurely of cardiomyopathy. It was subsequently found that the FXN gene is silenced at the chromatin level by the formation of heterochromatin and that this heterochromatin formation can be antagonized by histone deacetylase inhibitors (HDACi) (Chan et al., 2013). A recent proof-of-concept clinical study on ten patients with Friedreich ataxia demonstrated that FXN levels can be restored to those seen in asymptomatic carriers using the class III HDACi nicotinamide at a dose that is well tolerated by patients (Libri et al., 2014). Since carriers are asymptomatic, this degree of restoration of FXN expression might be expected to halt disease progression. Nicotinamide readily crosses the blood brain barrier and has previously been given at high doses for long periods to normal individuals without serious adverse effects (Gale et al., 2004; Knip et al., 2000). This study will be the first to provide clinical evidence for the efficacy and safety of nicotinamide in patients with Friedreich´s ataxia.

Scale for the Assessment and Rating of Ataxia (SARA) [ Time Frame: 1 year ]

The primary objective of the study is to evaluate the efficacy of daily doses of nicotinamide in slowing disease progression as measured by changes in the Scale for the Assessment and Rating of Ataxia (SARA) as compared with placebo in patients with Friedreich ataxia.

The SARA is a tool for assessing ataxia. It has eight categories with accumulative score ranging from 0 (no ataxia) to 40 (most severe ataxia). When completing the outcome measure each category is assessed and scored accordingly. Scores for the eight items range as follows:

Progression of quality of life measures via questionnaire EuroQol five dimensions questionnaire (EQ-5D) [ Time Frame: 1 year ]

This is a generic instrument, developed and validated by the EuroQoL Group (1990), in which the patient self-rates in particular his/her health status on a visual analogue scale (VAS); the best score is 100.

Modified FARS scores are defined as the sum of scores for bulbar function, upper limb coordination, lower limb coordination, and upright stability. The mFARS consists of three subscales, comprising a general score for ataxia, a score for activities of daily living and a neurological examination. The scores can be added to make a total score ranging from 0 to 159. A higher score indicates a greater level of disability.

CCFS includes two tests performed with the dominant hand,named the click test and the 9 holes pegboard test (9HPT). An electronic device was created to perform CCFS and to calculate the Z score by subtracting the expected time

Clinician's Global Impression-Change Scale (CGI-C) including comparison of change to the last visit [ Time Frame: 1 year ]

The Clinical Global Impression - Improvement scale (CGI-I) is a 7 point scale that requires the clinician to assess how much the patient's illness has improved or worsened relative to a baseline state at the beginning of the intervention. and rated as: 1. Very much improved; 2. Much improved; 3. Minimally improved; 4. No change; 5. Minimally worse; 6. Much worse; 7. Very much worse

Safety issues measured by appearance of AEs/SAEs [ Time Frame: 1 year ]

AEs may be volunteered spontaneously by the patient, or discovered as a result of general non-directed questioning by the study personnel or by physical examination.

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Layout table for eligibility information

Ages Eligible for Study:

18 Years and older (Adult, Older Adult)

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

No

Criteria

Inclusion Criteria:

Patients must have a molecular genetic diagnosis of Friedreich ataxia with a GAA- repeat expansion on both alleles of the FXN gene and a SARA Score >7 and <28 and age <50 years.

Patients must be ≥18 years old and have a weight of at least 50kg.

Written informed consent prior to study participation

A female subject is eligible to participate if she is of: Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea or of childbearing potential and agrees to

Exclusion Criteria:

Patients with any medical condition or illness that, in the opinion of the investigator would interfere with study compliance and/or impair the patient´s ability to participate or complete the study.

Any uncontrolled medical or neurological/neurodegenerative condition (other than Friedreich ataxia).

The subject received an investigational drug within 30 days prior to inclusion into this study.

Patients taking sodium valproate, tranylcypromine or any other known histone deacetylase inhibitor.

Use of vitamin B1 (thiamine), withdrawal should be at least 3 months prior screening or 5 half-lives, whichever is longer.

Use of vitamin B3 (nicotinamide), withdrawal should be at least 3 months prior screening.

If patients are taking idebenone or coenzyme Q10 (CoQ), this should be stable over the last three months and not changed during the study.

The subject is unwilling or unable to provide written informed consent and to follow the procedures outlined in the protocol.

For subjects who will undergo an MRI: Any contraindications to MRI such as, but not limited to cardiac pacemaker, implanted cardiac defibrillator, aneurysm clips, carotid artery vascular clamp, neurostimulator, implanted drug infusion devices, metal fragments or foreign objects in the eyes, skin or body, bone growth/fusion stimulator, cochlear, otologic implant, severe claustrophobia or any condition that would counterindicate an MRI scan.

Patients participating at start or have been within 30 days before start of study in another pharmacological and non-pharmacological clinical trial, excluding natural history / observational studies.

The subject is mentally or legally incapacitated.

Pregnant females as determined by positive [serum or urine] hCG test at Screening or prior to dosing. Participants of child-bearing age should use adequate contraception as defined in the study protocol.

The study results will be published in appropriate international scientific journals, and publishing details will be given in the clinical study agreement. The study will be registered and study results will be disclosed by the principal investigator in one or more public clinical study registry(ies), according to national/international use.